rs770377384
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_015164.4(PLEKHM2):c.1555G>T(p.Asp519Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,590,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D519V) has been classified as Uncertain significance.
Frequency
Consequence
NM_015164.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM2 | NM_015164.4 | c.1555G>T | p.Asp519Tyr | missense_variant | 9/20 | ENST00000375799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM2 | ENST00000375799.8 | c.1555G>T | p.Asp519Tyr | missense_variant | 9/20 | 1 | NM_015164.4 | P2 | |
ENST00000453804.1 | n.212-4340C>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151936Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000949 AC: 2AN: 210734Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 114116
GnomAD4 exome AF: 6.95e-7 AC: 1AN: 1438832Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 713526
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 151936Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74204
ClinVar
Submissions by phenotype
Dilated Cardiomyopathy, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PLEKHM2-related disease. This variant is present in population databases (rs770377384, ExAC 0.005%). This sequence change replaces aspartic acid with tyrosine at codon 519 of the PLEKHM2 protein (p.Asp519Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at